Design and synthesis of self-assembled ferulic acid-biotin nanoprodrugs with GSH/pH-responsive behavior and in vitro anticancer activity

Three FA-biotin conjugates were designed with 5-10 × higher cytotoxicity than FA. • These prodrugs self-assembled into nanoparticles, with FS6B forming optimal NPs. • FS6B NPs exhibited excellent stability and dual GSH/pH-responsive drug release. • FS6B NPs showed enhanced biotin receptor-mediated tumor targeting ability. • FS6B NPs exerted anticancer and anti-migration effects with minimal toxicity. Ferulic acid (FA) is widely recognized for its antioxidant and anti-inflammatory properties; however, its potential anticancer activity is limited by poor aqueous solubility and insufficient cellular uptake. In this work, a series of ferulic acid–biotin conjugates containing amino acid linkers of different lengths were synthesized and allowed to self-assemble into nanoparticles (FS4B, FS6B, and FS8B NPs). All nanoparticles had sizes below 200 nm, with FS6B NPs showing the best long-term stability for over 3 months. FS6B NPs exhibited glutathione- and pH-responsive release behavior and demonstrated over 10-fold stronger cytotoxicity toward 4T1 cells compared with free FA. Biotin-mediated cellular uptake was improved, accompanied by increased apoptosis induction. Furthermore, FS6B NPs significantly inhibited 4T1 cell migration, with a migration rate of 54.47%, in comparison with 72.51% for FA and 85.60% for the control. Meanwhile, FS6B NPs showed negligible toxicity toward normal cells and no detectable hemolytic activity. These results demonstrate that self-assembled FA-biotin nanoprodrugs possess favorable physicochemical properties and in vitro biological activity, providing insight into the structural modification and functional application of FA-based nanomaterials.